To our knowledge, this study is the first prospective investigation directly comparing a single UCB unit versus two-unit approach in adult hematologic malignancy patients treated with uniform RIC and supportive care including acute GvHD prophylaxis. Published work to date has included retrospective and more recently prospective studies supporting the administration of two units in adult patients in the myeloablative and RIC setting. Our study design used the availability of a single UCB unit of specified HLA match and nucleated cryopreserved cell dose (≥2.5×107/kg) as biologic assignment to one vs. two-unit UCB transplantation. Minimum required combined TNC dose of ≥3.0×107/kg was similar to previously reported requirements for two-unit recipients. However, as the threshold cell dose in the RIC setting has not been established, we chose a target dose of ≥2.5×107/kg above which patients were eligible for single unit transplantation, based on previous reports identifying safety in the myeloablative setting. The target cell dose selected is lower than minimum threshold cell doses previously reported by other investigators in two-unit studies in adults treated with non-myeloablative conditioning. Furthermore, this lower threshold cell dose allowed a larger proportion of study patients to proceed to transplant with a single unit graft. These observations may allow an adult patient lacking two UCB units of specified HLA match and cell content to proceed to transplantation with anticipated survival similar to that of 2 unit recipients.
Brunstein et al. reported the largest single institution series to date including 110 patients receiving UCB grafts after non-myeloablative conditioning with 85% of patients receiving a double unit UCB graft. A total of 35% of patients in this study were treated with ATG to reduce risk of graft rejection, which correlated with reduced risk of acute GvHD and higher TRM. Important challenges to analyses of clinical trials published to date include variance in patient selection, a potential lack of uniformity in patient characteristics in those receiving one vs. two-units with a large proportion of single unit recipients being pediatric patients, as well as changes over time in conditioning and GvHD prophylaxis including ATG administration.
The patients enrolled in this study are reflective of an adult hematology practice including the predominance of myeloid leukemia over lymphoid malignancy, and are comparable to other reports in terms of age and weight range. Of note, most patients included in reports on RIC outcomes with conventional adult donor and UCB grafts, had either no or prior autologous hematopoietic cell transplantation. Our study patient population had extremely high-risk (t-MN, 2nd AML) disease and was heavily pre-treated, including >50% of patients receiving prior autologous or allogeneic transplantation, implicating a possible higher risk of relapse- and non-relapse mortality. Despite this high risk, heavily pretreated patient population, EFS at three years was 28.6% in the 1-unit group and 39.1% in the 2-unit group and five-year EFS was 28.6% in the 1-unit group and 39.1% in the 2-unit group. These data support the use of RIC and UCB allogeneic transplantation as safe and effective treatment in these patients with advanced disease and extensive prior therapy. Additionally, these data compare favorably to previous single institution trials and larger retrospective series. Recent data published by the National Marrow Donor Program summarize transplant outcomes in adults treated with RIC and conventional adult-derived graft sources and show a 5-year OS of 23%.
A major concern for UCB transplant safety and efficacy for adult patients is the limited TNC and CD34+ progenitor cell content in the graft, generally a log lower than adult-derived grafts. Several studies have shown neutrophil engraftment after UCB transplantation correlating with graft TNC dose, CD34+ cell dose, CD3+cell dose and CD8+ cell dose. However, the influence of these graft cell populations is not seen consistently across all trials. CD34+ UCB graft cell dose has also been observed to correlate with EFS, OS, and lower TRM in some studies. From these studies the threshold of TNC dosing for UCB transplantation in the RIC setting has not been firmly established. We observed no differences in cumulative rates of attaining predominant donor chimerism at day 100 in this study, which were 72.4% in the 1-unit group compared to 75.2% observed in the 2-unit group. No differences were seen between the two groups in rates and kinetics of neutrophil and platelet engraftment. Additionally, we did not detect any statistically significant influence of TNC, CD34+, nor CD3+ UCB graft infused cell dose on engraftment or survival. This observation is consistent with the study by Brunstein et al, but differs from that reported in single and double unit UCB transplantation in the myeloablative setting.
Infusion of two UCB units did however significantly impact the relapse risk in this high risk patient population with 1-unit recipients having a relapse risk significantly higher than 2-unit recipients, suggesting strong graft-vs. malignancy effect of 2-unit UCB infusion as reported in prior retrospective studies. Sixteen (59.3%) patients in the 1-unit group in this study notably relapsed, compared to only 7 (30.4%) patients in the 2-unit group (p=0.045) in this study cohort of predominantly high risk or recurrent AML patients. Other investigators including Verneris et al. noted that relapse was significantly lower for early stage (1st or 2nd complete remission) patients who received two UCB units (RR 0.5, p<0.03) in 177 acute leukemia patients treated with myeloablative conditioning. The benefit of stronger graft vs. lymphoma effect has also been reported by the Eurocord-Netcord and lymphoma working party of the European group for Blood and Marrow Transplantation in 104 adult patients treated with 1 or 2-unit UCB after RIC with lower risk of relapse observed in recipients of double-unit UCB (p=0.03). Consistently, one UCB unit predominates in transplant recipients receiving two or more UCB units usually by 4–6 weeks after transplant. Infusion of the nonengrafting unit may augment UCB engraftment via immune activation and/or inhibition of recipient-mediated immune rejection. Since RIC transplantation depends on “allogeneic effect” to eliminate malignancy, each UCB unit represents an intact immune system with potential donor-recipient and donor-donor interactions that may render additional benefits of two-unit infusion, including enhanced graft vs. malignancy effects.
UCB transplantation, despite frequent HLA-mismatch, carries a surprisingly low risk for acute and chronic GvHD ; this risk could be conceivably higher in 2-unit recipients as previously reported. The combined rate of grade II–IV acute GvHD in this study was 44.9% in the two groups. Grade III acute GvHD rate was only 18.4%, and no patient demonstrated grade IV disease. The incidence of chronic GvHD was only 23.8%. We observed no significant association between the number of UCB units infused and occurrence of either acute or chronic GvHD. These observations may be attributable in part to administration of ATG to all study patients in this series.
This single institution feasibility study suggests that double UCB transplantation elicits stronger graft vs. malignancy effects in high risk adult patients with primarily myeloid leukemia. Nevertheless, single unit UCB transplantation at threshold nucleated cell dose exceeding 2.5×107/kg recipient weight remains a valid treatment option with equivalent survival rates for patients lacking two UCB units of specified HLA match and cell doses previously reported. While similar results have been reported in prior retrospective analyses by other groups, the data in this prospective study strengthens these observations: e.g. lower relapse risk after the infusion of two umbilical cord blood units, and similar survival outcomes in those transplanted with an adequate single unit or two units if one adequate unit is not available. There are also some differences: graft-versus-host disease may not be increased in recipients of two units, and graft cell dose may not be a risk factor for OS or EFS comparing the two groups. Whether limited patient numbers and/or length of follow up may underlie these differences, there are no prospective studies reported to date with UCB directly comparing single vs. double unit infusion in the setting of RIC. Given the small numbers of patients, prolonged accrual time, and the heterogeneity of the patient population in this study, definitive conclusions should be taken cautiously. Further studies are needed in larger multi-institutional prospective trials: 1) to more firmly establish the minimum safe threshold dose for single unit UCB in adult patients treated with RIC, and 2) to identify key parameters for graft selection in the two UCB unit setting that may contribute to enhanced graft vs. malignancy effects confirmed in this prospective single institution study.